Phase Ib Study of CD33 FPBMC in Patients With MRD+ AML or MDS (AML-MDS 001)

Phase Ib Study of Anti-CD3 x Anti-CD33 Bispecific Antibody (CD33Bi) Armed Fresh Peripheral Blood Mononuclear Cells (CD33 FPBMC) in Patients With Measurable Residual Disease (MRD)+ Acute Myeloid Leukemia or Myelodysplastic Syndrome

The purpose of this study is to understand the safety and estimate the efficacy of combining anti-CD3 x anti-CD33 bispecific antibody (CD33Bi) armed fresh peripheral blood mononuclear cells (CD33Bi FPBMC) for patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) where they still have detectable disease ("MRD+") after some treatment. Participants receive 4 weekly doses of CD33 FPBMC by intravenous infusion followed by 4-6 weeks of standard treatment with a hypomethylating agent (type of treatment such as decitabine or azacitidine) and possibly a drug called venetoclax. This is considered 1 cycle of study treatment and may be repeated up to 4 times during the study.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasm
• Intervention / Treatment: Drug: CD33 FPBMC

Detailed Description

Once subjects are determined to be eligible, white blood cells (lymphocytes) are collected via leukapheresis procedure. The T cells in the mononuclear cells are coated with bispecific antibody to activate the T cells and the mononuclear cells are reinfused into the patients so the T cells can multiply and kill AML/MDS cells.

At least 72 hours after the leukapheresis procedure, study treatment will start. Participants receive 4 weekly doses of CD33 FPBMC by intravenous infusion followed by 4-6 weeks of standard treatment with a hypomethylating agent (type of treatment such as decitabine or azacitidine) and possibly a drug called venetoclax. This is considered 1 cycle of study treatment and may be repeated up to 4 times during the study.

After about 2 cycles of study treatment, participants will have another leukapheresis procedure. Before, throughout and following study treatment, research blood will be collected to better understand immune response. Disease status will be checked regularly during and after study treatment.

• Study Type: Interventional
• Enrollment (Estimated): 23
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Ashley Donihee; Phone Number: 434-243-6377; Email: zwz6jm@uvahealth.org
• Study Contact Backup: Name: Avani Hopkins; Phone Number: 434-243-8108; Email: AJH7JQE@uvahealth.org

Study Locations

• United States
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • Recruiting
      • University of Virginia
      • Contact: Ashley Donihee; Phone Number: 434-243-6377; Email: zwz6jm@uvahealth.org
      • Contact: Avani Hopkins; Phone Number: 434-243-8108; Email: AJH7JQE@uvahealth.org
      • Principal Investigator: Daniel Reed, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adults: ≥18 years of age 2. Diagnosis of either:

1. Newly diagnosed or relapsed/refractory AML who have received either intensive induction chemotherapy or at least 2 cycles of a non-intensive options such as hypomethylating agent and venetoclax or other targeted agent
2. Relapsed/ refractory (R/R) MDS who have received at least 2 prior cycles of hypomethylating agent and venetoclax or single agent hypomethylating agent for at least 4 cycles

3. Relapsed/refractory (R/R) MDS/MPN overlap syndromes like CMML who have received at least 2 prior cycles of azacitidine and venetoclax or single agent hypomethylating agent for at least 4 cycles 3. For patients with targetable mutations (IDH1, IDH2, KMT2A, or FLT3): Receipt of and/or decision not to receive associated inhibitor.

   4. Patients with R/R MDS or R/R MDS/MPN overlap syndromes must have at least one of the following:

   1. Bone marrow blasts ≥ 5%
   2. Appearance of previously absent leukemic blasts in peripheral blood
   3. Absolute neutrophil count <1 x 109/L and 50% below best unsupported on-study value
   4. Platelet count <100 x 109/L and 50% below best unsupported on-study value
   5. Hemoglobin <11g/dL, and ≥2 g/dL reduction from best unsupported on-study value
   6. Increase of the volume of transfused red blood cells by more than 30% in an 8-week period
   7. Increase of the number of transfused platelet units by more than 30% in an 8-week period In the case of criteria 4-8 above, no reasonable alternative explanation such as drug toxicity should be identified.

   5. Patients with AML must have persistent or recurrent MRD positivity defined by presence of blasts ≥5% AND/OR disease detected by multiparametric flow cytometry (MFC) at a level of ≥0.1%, AND/OR persistent genomic mutations other than those found most with CHIP AND/OR persistent cytogenetic abnormalities related to underlying myeloid neoplasm

   6. Residual blasts must be positive for CD33 expression at any level. Note: Patients whose most recent disease-positive evaluation by flow cytometry showed CD33 expression but whose current assessment for MRD is only positive for genomics or cytogenetics may be included.

   7. Left Ventricular Ejection Fraction (LVEF) ≥ 45% at rest (MUGA or echocardiogram)

   8. Performance status ≤ 2 (ECOG Scale)

   9. Females of childbearing potential and males must agree to use an effective method for contraception for the duration of the treatment with study drug plus 90 days (duration of sperm turnover). Males must also abstain from sperm donations during study treatment and for at least 90 days after the last dose of study drug.

   10. Ability to provide informed consent and provision of written informed consent In order to be eligible to participate in the dose expansion portion of this study, an individual must meet all criteria that apply to the R/R MDS or R/R AML population (Newly diagnosed patients and patients with MDS/MPN overlap syndromes are not eligible for the expansion phase of the study).

In order to be eligible to participate in the dose expansion portion of this study, an individual must meet all criteria that apply to the R/R MDS or R/R AML population (Newly diagnosed patients and patients with MDS/MPN overlap syndromes are not eligible for the expansion phase of the study).

Exclusion Criteria:

1. Pregnancy or lactation
2. Prior treatment with anti-CD33 therapy
3. Patients who are being actively considered for stem cell transplant, unless participation in the study prior to the planned stem cell transplant is considered to be in the best interest of the patient in the opinion of the treating investigator in consultation with the transplant team. This does not exclude patients that may be eligible for stem cell transplant at some future (undetermined) date.
4. Past hematopoietic stem cell transplant (HSCT) with graft vs host disease requiring systemic immunosuppression other than low dose prednisone (10 mg) (or the equivalent dose of another immunosuppressant) within the 4 weeks before registration

5. Clinically significant organ dysfunction, defined as any of the following:

   • AST or ALT >3x the upper limit of normal (ULN)
   • Total bilirubin >1.5x the ULN, unless due to ongoing hemolysis or Gilbert's syndrome, in which case > 3.0 mg/dL
   • Absolute lymphocyte count (ALC) < 300 lymphocytes/microliter
   • Creatinine clearance <30 mL/min
   • Active serious infection not controlled by oral or intravenous antibiotics (e.g. persistent fever or lack of clinical improvement despite antimicrobial treatment).
6. Known human immunodeficiency virus (HIV) with detectable viral load.

7. Known hepatitis B surface antigen seropositive or known or suspected active hepatitis C infection

   a. Note: Patients who have isolated positive hepatitis B core antibody (ie, in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. Patients who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load.

8. Patients with a prior or concurrent malignancy whose natural history or treatment is anticipated to interfere with the safety or efficacy assessment of the investigational regimen (according to the treating investigator).
9. Treatment with any antileukemic agents or chemotherapy (other than hypomethylating agents or venetoclax) agents in the last 7 days or 5 half-lives (whichever is sooner) before study entry. Note: treatment with hydroxyurea may continue through the first cycle of study treatment.
10. Known allergy to hypomethylating agents
11. Blasts ≥ 25%

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CD33 FPBMC + hypomethylating agent with or without venetoclax; 4 weekly infusions of CD33 fresh peripheral blood mononuclear cells (FPBMC) followed by 4-6 weeks of hypomethylating agent with/without venetoclax.	Drug: CD33 FPBMC; Participants will receive up to 4 cycles of 4 weekly infusions of CD33 infusions followed by 4-6 weeks of a hypomethylating agent with or without venetoclax according to standard clinical care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DLTs	Escalation phase participants only	From start of treatment through 7 days after the 4th infusion (for each participant)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	Based on MRD status (AML cohort) and IWG criteria1 (MDS cohort)	During study treatment and for up to 3 years following intervention
Disease status	According to European LeukemiaNet (ELN) criteria (AML cohort) or IWG criteria (MDS cohort)	During study treatment and for up to 3 years following intervention
Progression free survival (PFS)	European LeukemiaNet (ELN) criteria (AML cohort) or IWG criteria (MDS cohort)	From baseline to disease progression or death from any cause, whichever comes first, assessed up to 3 yrs after last study drug administration
Adverse Events (AEs)	According to CTCAE v5	During and up to 30 days after last study treatment (all reportable AEs) and during long term follow-up (up to 3 years) for serious AEs considered related to study treatment

Collaborators and Investigators

• Sponsor: University of Virginia
• Investigators: Principal Investigator: Daniel Reed, MD, Assistant Professor; Study Director: Lawrence Lum, MD, DSc, IND Sponsor

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2026
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): July 1, 2031

Study Registration Dates

• First Submitted: November 17, 2025
• First Submitted That Met QC Criteria: December 3, 2025
• First Posted (Actual): December 8, 2025

Study Record Updates

• Last Update Posted (Actual): May 11, 2026
• Last Update Submitted That Met QC Criteria: May 5, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Bone Marrow Diseases; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Myelodysplastic-Myeloproliferative Diseases
• Other Study ID Numbers: 302332

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No